Method of antihypertensive chemotherapy utilizing 1-methyl-3keto-phenylquinuclidinium salts

ABSTRACT

Administration of pharmaceutically acceptable 1-methyl-3-keto-4phenylquinuclidinium salts is described as a chemotherapeutic method of treating hypertension in hypertensives. Daily doses ranging from 10 mg/kg to 300 mg/kg are effective in producing an antihypertensive effect in the latter.

United States Patent [1 1 Hong [ Jan. 14, 1975 METHOD OFANTIHYPERTENSIVE CHEMOTHERAPY UTILIZING l-METHYL-3-KETO-4-PHENYL-QUINUCLIDINIUM SALTS [75] Inventor:

[73] Assignee: Miles Laboratories, Inc., Elkhart,

Ind.

22 Filed: Dec.8, 1972 21 Appl.No.:3l3,439

Enrique Hong, Mexico, Mexico [52] US. Cl. 424/267 [51] Int. Cl A6lk27/00 [58] Field of Search 424/267 [56] References Cited OTHERPUBLICATIONS Perrine, J. Org. Chem, 22, pages 1484-1489, 1957.

Primary Examiner-Albert T. Meyers Assistant ExaminerDaren M. StephensAttorney, Agent, or Firm-Myron B. Sokolowski [57] ABSTRACT 8 Claims, N0Drawings METHOD OF ANTIHYPERTENSIVE CHEMOTHERAPY UTILIZINGl-METHYL-3-KETO-4- PHENYLQUINUCLIDINIUM SALTS BACKGROUND OF THEINVENTION 1. Field of the Invention The clinical manifestation ofhypertension is an elevated systemic arterial pressure. In some cases ofhypertension, therapy can be focused on the correction of primaryetiological factors, as in pheochromocytoma or Cushings disease. In mostcases, however, the etiology is obscure, and therapy can be directedonly to decreasing the abnormal pressure. A common method of achievingthe latter is chemotherapeutic administration of an antihypertensivedrug. The disclosed use of pharmaceutically acceptable1-methyl-3-keto-4- phenylquinuclidinium salts is such a method ofchemotherapy.

2. Description of the Prior Art The prior art relating tochemotherapeutic methods of treating hypertensives is discussedcomprehensively in the following references: Nickerson, M.,Antihypertensive Agents and the Drug Therapy of Hypertension, in ThePharmacological Basis of Therapeutics, 4th Edition, L. S. Goodman and A.Gilman, Editors, New York, Macmillan, 1970, Chapter 33, pages 728-744;and Nickerson, M., Drugs Inhibiting Adrenergic Nerves and StructuresInnervated by Them, III. Adrenergic Neuron Blocking Agents, op. cit.,Chapter 26, pages 570-580.

All known antihypertensive agents produce significant untoward sideeffects, especially the two mainstay drugs reserpine and guanethidine.Reserpine, a rauwolfia alkaloid, is an adrenergic neuron blocking agentwhich, in addition to affecting arterial blood pressure, causes untowardside effects referable to the central nervous and gastrointestinalsystems. Even at low doses reserpine can produce incidence of nightmaresand psychic depression. Reserpine commonly produces in creasedgastrointestinal tone and motility, gastric hyperacidity, and diarrhea.Extrapyramidal disturbances can accompany high'doses.

Guanethidine depresses the function of postganglionic adrenergic nerves.Its action is prolonged and its effects are cumulative over extendedperiods. Tolerance to the drug is observed in percent of patients underchronic treatment, and higher doses are generally required in thesecases. The'most important complication in guanethidine therapy ispostural hypotension, although the following are frequently observed:exertional weakness, bradycardia, nasal congestion and diarrhea.

The compounds of the present invention, 1-methyl-3-keto-4-phenylquinuclidinium salts, have the following structuralformula:

where X is a nontoxic anion. These compounds are not relatedstructurally to known antihypertensive agents,

nor are they related to known adrenergic neuron blocking andnorepinephrine depleting agents.

The synthesis of 1-methyl-3-keto-4- phenylquinuclidinium salts isdescribed in J. Org. Chem., 22:1484-1489, at 1487-1488 (1957) by T. D.Perrine. In this publication, preliminary reports are included that3-keto-4-phenylquinuclidine and 4- phenylquinuclidine exhibit analgesicaction, but that the latter is quite toxic. A rather thorough review ofquinuclidine chemistry and pharmacology can be found in Mashkowsky etal., Prog. Drug Rcs. l3:293339 (1969).

The pharmacology of l-methyl-3-keto-4- phenylquinuclidinium salts per sehas not been published.

SUMMARY OF THE INVENTION One essential feature of this discovery is theantihypertensive effect of pharmaceutically acceptable 1-methyl-3-keto-4-phenylquinuclidinium salts when administered tohypertensive mammals. Another essential feature is the production ofadrenergic neuron blockade and norepinephrine depletion at neuroeffectorsites by administration of these compounds. Administration of aneffective amount, ranging between 10 to 300 mg per day, depending on theseverity of the case, is effective in reducing systemic arterialpressure in hypertensives to normal levels. In particular, 1-methy1-3-keto-4-phenylquinuclidinium bromide is especially active as anantihypertensive agent. In comparative tests with guanethidine as areference, 1-methyl-3-keto-4- phenylquinuclidinium salts exhibit greaterefficacy as adrenergic neuron blocking and norepinephrine depletingagents.

Because utilization of pharmaceutically acceptable1-methyl-3-keto-4-phenylquinuclidinium salts in the disclosed methoddoes not involve the central nervous system and is effective atrelatively low doses, the complications arising in therapy withreserpine and guanethidine, respectively, can be avoided.

Dose forms of non-toxic 1-methyl-3-keto-4- phenylquinuclidinium saltscan be conveniently prepared by the addition of pharmaceuticallyacceptable carriers generally used in formulations. Dose forms can beprepared in the solid or liquid state by methods known in the art fororaLintravenous and other methods of administration.

DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLE 1 The method ofproducing adrenergic neuron blockage utilizing1-methyl-3-keto'4-phenylquinuclidinium bromide was compared in twoexperimental models with the following reference compounds:

clidinium bromide (Steinbach, US. Pat. No. 2,648,667 [1953]); oxylidine(Steinbach, op. cit.); 3- (3-dimethylaminopropoxy) quinuclidinedimethoxide (Collins et al., J. Pharm. Sci., 56: 1668 [1967]); andquanethidine.

A. Finklemans Preparation (J. Physiol. [Lond.], :145-157 [1930]).Responses of rabbit ileum preparations to periarterial stimulation wererecorded before and every ten minutes after the addition to the tissuechamber of a given concentration of the compound being tested.1-methy1-3-keto-4-pheny1quinuclidinium bromide and guanethidine blockedileum responses to periarterial stimulation to 50 percent of control in14 minutes at a concentration of 1 mcg/ml, while clidinium bromide,3-benzoyloxyquinuclidine hydrochloride and3-(3-dimethylaminopropoxy)quinuclidine dimethiodide did not impair ileumresponses after contact with the preparations for one hour at aconcentration of meg/m1.

B. Nictitating Membrane Model. Nicitating membrane responses to preandpost-ganglionic sympathetic stimulation (0.2 msec. duration, 10 cyclesper sec., and supramaximal voltage for 40 sec.) were recorded fromanestethized cats before and after the intravenous administration of 3.1mg/kg of the compound to be tested. 1-methy1-3-keto-4-phenylquinuclidinium bromide and guanethidine blocked the nictitatingmembrane responses to both preand post-ganglionic sympatheticstimulation by more than 40 percent; 3-(3-dimethylaminopropoxy)-quinuclidine dimethiodide antagonized only the responses to preganlionicstimulation, and clidinium bromide and 3-benzoyloxyquinuclidinehydrochloride did not modify nictitating membrane responses to eitherpre or post-ganglionic sympathetic stimulation.

EXAMPLE 2 The method of depleting norepinephrine levels utilizing1-methy1-3-keto-4-phenylquinuclidinium bromide was compared toguanethidine according to the procedure described by Phillips et al. inJ. Pharm. Sci., 58:572574 (1969). Heart norepinephrine levels weredetermined in albino rats at 8 and 24 hr after intraperitonealadministration of 31 mg/kg of 1-methy1-3-keto- 4-phenylquinuclidiniumbromide or guanethidine. Norepinephrine levels in relation to those ofcontrol animals at 8 and 24 hr after drug administration wererespectively: 25 and 53% for the 1-methyl-3-keto-4- quiniclidiniumbromide, and 8 and 61% for guanethidine.

EXAMPLE 3 The antihypertensive effect of 1-methyl-3-keto-4-phenylquinuclidinium bromide and guanethidine was assessed in mongreldogs which were made hypertensives by chronic administration ofmecamylamine according to the procedure described by Pardo and Vidrio inJ. Pharmacol. Exp. Ther. 144:124-130, 1964. Control systolic anddiastolic blood pressures were recorded three times per week for aperiod of four weeks. The dogs were then divided into two groups, one ofwhich received 1-methyl-3-keto-4- phenylquiniclidinium bromide in dailyoral doses for 4 weeks, and the other guanethidine. Systolic anddiastolic blood pressures were recorded three times per week for anotherperiod of 4 weeks after administration of the drugs. Mean blood pressurevalues obtained during the control period were compared with the mean ofrecordings obtained during treatment. Table I shows the resultsobtained. No central nervous system effects were observed in dogstreated with either 1- methyl-3-keto-4-phenylquinuclidinium bromide orguanethidine throughout the experiment.

Table 1 Control Treatment Num- Systolic] Systolic/ ber 1 Daily Dose ofDiastolic Diastolic Compound (mg/kg, p.o.) dogs (mmHg) (mmHg)1-methy1-3- 1.0 2 185/99 155/68 keto-4-phenyl -quinuc idi 3.1 2 177/87141/62 mum bromide 10.0 2 186/97 132/56 Guanethidine 1.0 2 183/97 158/703.1 3 195/105 172/88 3 179/92 /63 EXAMPLE 4 Relaxation of nictitatingmembranes was assessed in unanesthetized cats under chronicadministration of either l-methyl-3-keto-4-phenylquinuclidinium bromideor guanethidine. Relaxation was evaluated in terms of the percent of thegreater eye diameter occupied by the membrane. Photographs of the eyeswere taken before and at various times after the daily subcutaneousinjection of the compounds at 3.1 mg/kg for 29 days. Six cats were usedfor each compound. Acute relaxation of nictitating membranes reached amaximum after the fifth injection of the two compounds. The valuesobserved were 39 percent in cats treated with 1-methyl-3-keto-4-phenylquinuclidinium bromide and 28.5 percent in catsreceiving guanethidine. The maximal residual effect (nictitatingmembrane relaxation 24 hr after drug administration) was also observedafter the fifth dose forboth drugs. Animals receiving 1-methyl-3-keto-4-phenylquinuclidium bromide showed a maximal relaxationof 38.5 percent, an effect which did not decrease significantlythroughout the experiment. Cats treated with guanethidine showed amaximal relaxation of 30 percent, which by the end of the experiment haddecreased to 15 percent. No central nervous system effects were observedin any of the two groups of cats throughout the experiment.

EXAMPLE 5 Toxicity of 1-methy1-3-keto-4-phenylquinuclidinium bromide andguanethidine was determined by administration of graduatedintraperitoneal doses to mice. The LD and 95 percent confidence limitwas 243 (202-292) mg/kg for 1-methy1-3-keto-4- phenylquinuclidiumbromide, and 184 (-212) mg/kg for guanethidine.

What is claimed is:

l. A method of producing an antihypertensive effect in a hypertensivemammal, which comprises administering to said mammal an effective amountof a pharmaceutically acceptable l-methyl-3-keto-4- phenylquinuclidiniumsalt. 2. A method as in claim 1 wherein said salt islmethy1-3-keto-4-phenylquinuclidinium bromide.

3. A method as in claim 1 wherein said amount ranges from 10 mg/kg to300 mg/kg per day.

4. A method as in claim 1 which further comprises: administering saidsalt with a pharmaceutically acceptable carrier. 5. A method as in claim4 wherein said carrier is a solid.

6. A method as in claim 4 wherein said carrier is a liquid.

7. A method as in claim 1 wherein said salt is administered orally.

8. A method as in claim 1 wherein said salt is administeredintravenously.

2. A method as in claim 1 wherein said salt is1-methyl-3-keto-4-phenylquinuclidinium bromide.
 3. A method as in claim1 wherein said amount ranges from 10 mg/kg to 300 mg/kg per day.
 4. Amethod as in claim 1 which further comprises: administering said saltwith a pharmaceutically acceptable carrier.
 5. A method as in claim 4wherein said carrier is a solid.
 6. A method as in claim 4 wherein saidcarrier is a liquid.
 7. A method as in claim 1 wherein said salt isadministered orally.
 8. A method as in claim 1 wherein said salt isadministered intravenously.